Process for Preparing Quinolin-2-yl-phenylamine Derivatives and their Salts

ABSTRACT

without a metal catalyst, and (ii) to soluble mineral acid or sulfonic acid salts of (8-chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine.

The present invention relates (i) to a process for the preparation ofquinolin-2-yl-phenylamine derivatives of formula (I)

without a metal catalyst, and (ii) to soluble mineral acid or sulfonicacid salts of (8-chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine.

The international patent application WO 2010/143169 describesquinolin-2-yl-phenylamine derivatives which show inhibition of theproduction of the HIV core antigen p24 in HIV infected PBMCs (peripheralblood mononuclear cells). A once-day orally available first-in-classquinolin-2-yl-phenylamine derivative that inhibits HIV replicationthrough this entirely new mechanism is(8-chloro-quinolin-2-yl)-(4-trifluoromethoxy-phenyl)-amine, also knownas ABX-464. In contrast to the numerous antiviral drugs that arecurrently available for HIV treatment, this quinolin-2-yl-phenylaminederivative is the first agent that affects the production stage of HIV-1replication by preventing the export of viral RNA from the nucleus tothe cytoplasm in infected cells. Moreover, this drug candidate is highlyselective and doesn't affect normal cellular splicing. Preclinical dataindicated sustained reduction of viral load which lasted for severalweeks after cessation of treatment. In phase I trials, it was welltolerated at dose levels up to 200 mg without clinically significantabnormal results. The drug candidate is currently in phase IIevaluation.

The chemical structure of the drug candidate(8-chloro-quinolin-2-yl)-(4-trifluoromethoxy-phenyl)-amine, themolecular weight and formula are as follows:

WO 2010/143169 further discloses the preparation ofquinolin-2-yl-phenylamine derivatives through two routes in the presenceof a metal catalyst, such as Pd(OAc)₂ or Pd₂dba₃. Example 5 describesthe preparation of(8-chloro-quinolin-2-yl)-(4-trifluoromethoxy-phenyl)-amine (compound 90)according to route (A) and includes a final purification step by columnchromatography to yield the pure compound.

The comparative example based on WO 2010/143169 shows that, although2,8-dichloroquinoline was completely converted, the yield was limited toa maximum of 65%. It was further found by the inventors thatsimultaneous side reactions account for the relative low yield as theylead to undesired by-products. Moreover, the existence of theseby-products makes pre-purification by flash chromatography inevitable.The results of the palladium mediated coupling according to Example 5 ofWO 2010/143169 can be summarized as follows:

The rework of this procedure by the present inventors confirmed thecompound, but since purification by column chromatography furnished therespective compound only in 95% purity due to undesired by-products, arecrystallization was further applied. Hereby the compound was obtainedin a chemically pure crystalline form. Thereafter, the solubility of thecompound was analyzed by the inventors in aqueous solutions withdifferent pH-values simulating distinct physiological conditions. Theoutcome reveals a virtual insolubility of the compound in aqueoussolution, independent of its pH value.

In view of the above and considering that reactions utilizing palladiumas metal catalyst in the last stage are disfavored according ICHguidelines, an improved process for the preparation ofquinolin-2-yl-phenylamine derivatives, and soluble forms or formulationsof (8-chloro-quinolin-2-yl)-(4-trifluoromethoxy-phenyl)-amine aredesired.

Therefore, the present invention concerns a process for preparingquinolin-2-yl-phenylamine derivatives, and soluble salts of(8-chloro-quinolin-2-yl)-(4-trifluoromethoxy-phenyl)-amine.

According to a first embodiment, a subject-matter of the presentinvention relates to a process for preparing a compound of formula (I)

wherein:

-   R independently means a hydrogen atom, a halogen atom or a group    selected from a (C₁-C₃)alkyl group, a —NR₁R₂ group, a    (C₁-C₃)fluoroalkoxy group, a phenoxy group or a (C₁-C₄)alkoxy group,    with R₁ and R₂ are independently a (C₁-C₃)alkyl group;-   R′ is a hydrogen atom, a halogen atom except fluorine, or a group    selected from a (C₁-C₃)alkyl group, preferably a chlorine atom or a    bromine atom;-   R″ is a hydrogen atom or a (C₁-C₄)alkyl group, preferably a hydrogen    group;-   R′″ is a hydrogen atom, a halogen atom, or a group selected from a    (C₁-C₃)alkyl group or a (C₁-C₄)alkoxy group, preferably a hydrogen    atom, a chlorine atom or a bromine atom;-   n is 1, 2 or 3, preferably 1 or 2; and-   n′ is 1 or 2, preferably 1;    which comprises the step of reacting a compound of formula (II)

wherein:

-   R′, R′″ and n′ are defined as in formula (I); and-   L means a leaving group, preferably selected from a halogen atom, in    particular selected from a fluorine atom, a chlorine atom or a    bromine atom; preferably a fluorine atom or a chlorine atom;    with a compound of formula (III)

wherein R″, R, and n are defined as in formula (I); andwherein the compound of formula (III) is present in excess and no metalcatalyst is present, e.g. no palladium catalyst, such as Pd(OAc)₂ orPd₂dba₃, as described in the prior art.

According to another aspect, the present invention relates to processfor preparing a compound of formula (I) as defined above, wherein

-   R is a (C₁-C₃)fluoroalkoxy group, preferably a trifluoromethoxy    group;-   R′ is a chlorine atom or a bromine atom;-   R″ is a hydrogen atom;-   R′″ is a hydrogen atom, a chlorine atom or a bromine atom; and-   n and n′ are 1.

According to a further aspect, the present invention relates to processfor preparing a compound of formula (I) as defined above, wherein

-   R′ is a chlorine atom-   R is a trifluoromethoxy group;-   R″ and R′″ are independently a hydrogen atom; and-   n and n′ are 1.

In particular, the present invention relates to a process for preparing(8-chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine and optionallyits pharmaceutically acceptable salt.

The idea was to approach the desired compounds of formula (I) not bypalladium mediated cross-coupling reaction but by nucleophilic aromaticsubstitution. This alternative reaction mechanism should avoid formationof the illustrated side products and circumvent problems with metalresidues after purification. Due to the limited electron withdrawingpower of the present pyridine moiety and the relative weakness of ananiline nucleophile it was surprising that the nucleophilic aromaticsubstitution mechanism works in the present case. However, furtherattempts in various solvents proceeded only with moderate conversioneven at elevated temperatures.

According to the present invention, the ratio of solvent was reduced andthe utilization of a heterogeneous inorganic base discarded.Surprisingly it was found that the basicity of the aniline derivative,in particular the 4-(trifluoromethoxy)aniline itself was sufficient, andthe best result was obtained by performing the conversion in the pureaniline derivate, i.e. pure 4-(trifluoromethoxy)aniline, which proceededvery fast and clean in a spot to spot reaction. Subsequent experimentswere performed with the aniline derivative and different solvents. Inparticular, good results were obtained with (C₁-C₄)alcohols. Forexample, the conversion in methanol solution proceeded very clean, butwith a prolonged reaction time compared to the reaction without asolvent. With e.g. isopropanol as solvent, the reaction time wasprolonged in an acceptable frame compared to the reaction without asolvent, and the conversion proceeded as clean as in the pure reactant.

Therefore, according to another aspect, the present invention relates toa process for preparing a compound of formula (I) as defined above,wherein the reaction is carried out in the presence of an(C₁-C₄)alcohol, preferably butanol or propanol, in particular t-butanolor isopropanol, more in particular isopropanol.

According to a further aspect, the present invention relates to aprocess for preparing a compound of formula (I) as defined above,wherein the reaction is carried out at a temperature between 25° C. and130° C., preferably at a temperature between 80° C. and 100° C., inparticular at about 90° C. According to the present invention, the term“about” means+/−5° C., i.e. from 85° C. to 95° C., preferably at 90° C.

According to a further aspect, the present invention relates to aprocess for preparing a compound of formula (I) as defined above,wherein the reaction is carried out for 0.5 h to 15 h, preferably for0.5 h to 13 h, in particular for 3 h to 4 h.

According to another aspect, the present invention relates to a processfor preparing a compound of formula (I) as defined above, wherein thereaction is carried out with 1 mole of compound (II) and 2-5 mole ofcompound (III), in particular the reaction is carried out with 1 mole ofcompound (II), 2-5 mole of an (C₁-C₄) alcohol, and 2-5 mole of compound(III), preferably with 1 mole of compound (II), 5 mole of an (C₁-C₄)alcohol, and 2-3 mole of compound (III).

According to a more specific aspect, the present invention relates to aprocess for preparing a compound of formula (I) as defined above,wherein the reaction is carried out with 1 mole of compound (II), 5 moleof an (C₁-C₄) alcohol, and 2-3 mole of compound (III) at a temperatureof about 90° C., as defined above.

The isolation of the desired product can be achieved e.g. throughprecipitation. The reaction mixture can, therefore, be diluted withadditional (C₁-C₄)alcohol, as defined above, preferably isopropanol, andafter the addition of e.g. water preferably a fine and homogenousprecipitate can be obtained. The collected and dried filter cake inparticular yields a product in high purity (>99.0%). Preferably, beforecarrying out any recrystallization steps, the process according to thepresent invention yields a product having a purity of more than 90%,preferably more than 95%, e.g. between 95 to 99%, in particular 99%.Preferably, before carrying out any recrystallization steps, the processaccording to the present invention yields a product having an totalimpurity content of not more than 5%, preferably not more than 1%.Further purification can be obtained by recrystallization from anon-polar, aprotic solvent, e.g. cyclohexane or benzene, providing acrystalline product having a purity of ≥99.5%, preferably ≥99.9%.

Therefore, according to another aspect, the present invention relates toa process for preparing a compound of formula (I) as defined above,wherein the process further comprises the step of precipitating thecompound of formula (I), preferably by adding water.

According to still another aspect, the present invention relates to aprocess for preparing a compound of formula (I) as defined above,wherein the process further comprises the step of recrystallizing, andoptionally drying, the precipitated compound of formula (I). Therecrystallization of the compound can e.g. be carried out in anon-polar, aprotic solvent, e.g. cyclohexane or benzene, preferablycyclohexane.

Generally, the herein described inventive process shows surprisinglyhigh product selectivity, the avoidance of metal catalysts, a simpleworkup and a high purity grade of the isolated product. It is easilyapplicable for each scale (gram to multi kilogram) and shows very goodreproducibility. In addition, the recrystallization of the productobtained by the inventive process provides the product in very goodcrystallinity.

According to another aspect, the present invention relates to a processfor preparing a compound of formula (I) as defined above, wherein theprocess further comprises the step of preparing a pharmaceuticallyacceptable salt of the compound of formula (I). Suitablepharmaceutically acceptable salts are e.g. hydrobromide,trifluoroacetate, ascorbate, hydrochloride, triflate or mesylate.

According to another aspect, the present invention relates to a processfor preparing a compound of formula (I) as defined above, wherein theprocess further comprises the step of formulating the compound offormula (I), and optionally its pharmaceutically acceptable salt, with agenerally known pharmaceutically acceptable carrier, e.g. for thepreparation of tablets, solutions, emulsions, microemulsions oroil-in-water emulsions, e.g. for enteral or parenteral administration,in particular for oral administration. A preferred formulation is atablet for oral administration.

According to a second embodiment, a subject-matter of the presentinvention relates to a specific polymorphic form of the free base of(8-chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine, which isobtainable by a process of the present invention. The specificpolymorphic form of the free base of(8-chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amin is named “FormI” according to the present invention.

Form I is characterized by a single endotherm with an onset temperatureof 120° C. (±2° C.) and a peak temperature of 121° (±2° C.) in the DSCthermogram (FIG. 4). In particular, Form I is alternatively oradditionally characterized by characteristic signals in the x-ray powderdiffractogram (FIG. 5) at angles 7.3, 14.6 and 24.8. Furthercharacteristic signals are preferably at angles 18.3 and 23.0.Additional characteristic signals are preferably at angles 28.3 and29.5. In another aspect, Form I is characterized by the x-ray powderdiffractogram as depicted in FIG. 5.

Therefore, according to another aspect, the present invention relates toa polymorphic form of the free base of(8-chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine, characterizedby a single endotherm with an onset temperature of 120° C. (±2° C.) anda peak temperature of 121 (±2° C.) in the DSC thermogram and/orcharacterized by characteristic signals in the x-ray powderdiffractogram at angles 7.3, 14.6 and 24.8. Preferably, the polymorphicform is characterized by characteristic signals in the x-ray powderdiffractogram at angles 7.3, 14.6, 18.3, 23.0 and 24.8, and inparticular at angles 7.3, 14.6, 18.3, 23.0, 24.8, 28.3 and 29.5.Remarkable peaks can also be seen at angles 18.6, 22.3, 24.1, 29.0 and42.6. In another aspect Form I is characterized by the x-ray powderdiffractogram as depicted in FIG. 5.

In another aspect the present invention relates to a pharmaceuticalcomposition comprising Form I of(8-Chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine. Preferablythe pharmaceutical composition is a composition for oral administrationsuch as a tablet.

(8-Chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine, in particularthe above-described Form I, can preferably be obtained by the followingprocess steps:

-   (a) preparing a mixture of 2.5 equivalents    4-(trifluoro-methoxy)-aniline and 1 equivalent    2,6-dichloro-quinoline in 5 equivalents isopropanol;-   (b) heating the mixture of step (a) to 90° C. for 3-4 hours;-   (c) precipitating the reaction product of step (b) by the addition    of isopropanol followed by the addition of water;-   (d) drying the precipitated reaction product of step (c); and-   (e) recrystallizing the dried reaction product of step (d) in    cyclohexane.

Preferably, before carrying out any recrystallization steps, the processaccording to the present invention yields Form I of(8-Chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine having apurity of more than 90%, preferably more than 95%, e.g. between 95 to99%, in particular 99%. Preferably, before carrying out anyrecrystallization steps, the process according to the present inventionyields Form I of(8-Chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine having antotal impurity content of not more than 5%, preferably not more than 1%.Further purification can be obtained by recrystallization from anon-polar, aprotic solvent, e.g. cyclohexane or benzene, providing acrystalline product having a purity of ≥99.5%, preferably ≥99.9%.

According to a third embodiment, a subject-matter of the presentinvention relates to a mineral acid or sulfonic acid salt of(8-chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine. The free baseof the compound can e.g. be obtained according to the method disclosedin Example 5 of WO 2010/143169 or as described in the presentspecification.

According to another aspect, the present invention relates to mineralacid of (8-chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine,wherein the mineral acid is selected from hydrochloric acid or sulfuricacid. In a particular embodiment of the present invention the mineralacid is sulfuric acid.

According to another aspect, the present invention relates to a sulfonicacid of (8-chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine,wherein the sulfonic acid is selected from an alkylsulfonic acid orarylsulfonic acid, in particular wherein the alkylsulfonic acid isselected from mesylate, triflate or edisylate, more in particularedisylate, or wherein the arylsulfonic acid is selected from besylate ortosylate.

According to a forth embodiment, a subject-matter of the presentinvention relates to a pharmaceutical composition containing a mineralacid or sulfonic acid salt of(8-chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine, as definedabove, and a generally known pharmaceutically acceptable carrier, e.g.for the preparation of tablets, solutions, emulsions, microemulsions oroil-in-water emulsions, e.g. for enteral or parenteral administration,in particular for oral administration. A preferred formulation is atablet for oral administration.

According to another aspect, the present invention relates to saidpharmaceutical composition for use in a method for treating an HIVinfection.

In a preferred embodiment of the present invention said pharmaceuticalcomposition is in the form of an orally administrable pharmaceuticalcomposition, in particular for treating an HIV infection.

The following figures and examples shall illustrate the presentinvention without limiting its scope.

FIGURES

FIG. 1 shows a 1H-NMR spectrum of the free base of(8-chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine.

FIG. 2 shows a FT-IR spectrum of the free base of(8-chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine.

FIG. 3 shows a GC-MS spectrum of the free base of(8-chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine.

FIG. 4 shows a DSC thermogram of the free base of(8-chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine.

FIG. 5 shows a XRPD diffractogram of the free base of(8-chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine.

FIG. 6 shows a 1H-NMR spectrum of the HCl addition salt of(8-chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine.

FIG. 7 shows a FT-IR spectrum of the HCl addition salt of(8-chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine.

FIG. 8 shows a 1H-NMR spectrum of the H₂SO₄ addition salt of(8-chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine.

FIG. 9 shows a FT-IR spectrum of the H₂SO₄ addition salt of(8-chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine.

FIG. 10 shows a 1H-NMR spectrum of the besylate addition salt of(8-chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine.

FIG. 11 shows a FT-IR spectrum of the besylate addition salt of(8-chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine.

FIG. 12 shows a 1H-NMR spectrum of the tosylate addition salt of(8-chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine.

FIG. 13 shows a FT-IR spectrum of the tosylate addition salt of(8-chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine.

FIG. 14 shows a 1H-NMR spectrum of the edisylate addition salt of(8-chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine.

FIG. 15 shows a FT-IR spectrum of the edisylate addition salt of(8-chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine.

FIG. 16 shows a DSC thermogram of the HCl addition salt of(8-chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine.

FIG. 17 shows a XRPD diffractogram of the HCl addition salt of(8-chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine.

FIG. 18 shows a DSC thermogram of the H₂SO₄ addition salt of(8-chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine.

FIG. 19 shows a XRPD diffractogram of the H₂SO₄ addition salt of(8-chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine.

FIG. 20 shows a DSC thermogram of the besylate addition salt of(8-chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine.

FIG. 21 shows a XRPD diffractogram of the besylate addition salt of(8-chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine.

FIG. 22 shows a DSC thermogram of the tosylate addition salt of(8-chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine.

FIG. 23 shows a XRPD diffractogram of the tosylate addition salt of(8-chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine.

FIG. 24 shows a DSC thermogram of the hemiedisylate addition salt of(8-chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine.

FIG. 25 shows a XRPD diffractogram of the hemiedisylate addition salt of(8-chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine.

FIG. 26 shows the DVS diagram of the free base of(8-chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine.

FIG. 27 shows the DVS diagram of the HCl addition salt of(8-chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine.

FIG. 28 shows the DVS diagram of the H₂SO₄ addition salt of(8-chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine.

FIG. 29 shows the DVS diagram of the besylate addition salt of(8-chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine.

FIG. 30 shows the DVS diagram of the tosylate addition salt of(8-chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine.

FIG. 31 shows the DVS diagram of the hemiedisylate addition salt of(8-chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine.

EXAMPLES 1. Analytical Methods 1.1 HPLC/UV Chromatography

-   Instrument: Agilent 1200-   Injection volume: 3 μl-   Solvent A: acetonitrile-   Solvent B: KH₂PO₄ (10 mM) pH2.3-   Flow: 1.5 ml/min-   Temperature: 25° C.-   Column: Supelco Discovery C18, 150*4.6 mm, 5 μm

time [min] solvent B [%] 0.00 75 4.00 20 15.00 20 15.50 75 17.00 75

1.2 GC-MS

-   Instrument: HP6890 coupled with MS detector HP5973-   Injection volume: 2 μl-   Column: Agilent 19091S-431 HP-5MS UI-   Injector temp: 250° C.-   Injection: 2 μl-   Mode: split ( 1/30)-   Temperature program: 50-280° C., 17° C./min; runtime 15.53 min

1.3 Nuclear Magnetic Resonance (NMR) Spectroscopy

NMR-measurements were performed with Varian Mercury 400 Plus NMRSpectrometer, Oxford AS, 400 MHz. The result is shown in FIG. 1. The NMRspectrum was characterized by the following signals:

1H NMR (400 MHz, CDCl₃) δ ppm 6.87 (m, 2H); 7.23 (m, 3H); 7.55 (dd,J=8.01, 1.28 Hz, 1H); 7.72 (dd, J=7.52, 1.28 Hz, 1H); 7.90 (m, 3H).

1.4 Infrared (FT-IR) Spectroscopy

IR-measurements were performed with Thermo Nicolet, Avatar 330 FT-IR.The result is shown in FIG. 2. The IR-spectrum was characterized by thefollowing signals:

3406; 1626; 1606; 1535; 1506; 1475; 1425; 1392; 1257; 1217; 1146; 1001;849; 822; 795; 754; 719; 673; 663; 631 cm⁻¹.

1.5 Differential Scanning Calorimetry (DSC)

-   Instrument: Mettler Toledo DSC 822E coupled with a Mettler Toledo    Gas-Flow-Controller TS0800GC1 (Mettler-Toledo GmbH, Gieflen,    Germany)-   Aluminium crucible: 40 μL-   Lid: Perforated-   Temperature range: 30° C. to 350° C.-   Heating rate: 10° C./min-   Nitrogen flush: 50 mL/min-   Software: STARe Version. 8.10-   Interpretation: Endothermic modus

1.6 X-Ray Powder Diffraction (XRPD)

The sample was analyzed on a D8 Advance X-ray powder diffractometer(Bruker-AXS, Karlsruhe, Germany). The sample holder was rotated in aplane parallel to its surface at 20 rpm during the measurement. Furtherconditions for the measurements are summarized in the table below. Theraw data were analyzed with the program EVA (Bruker-AXS, Germany). Thesamples were layered onto a silicon specimen holder.

standard measurement radiation Cu Kα (λ = 1.5406 Å) source 38 kV/40 mAdetector Vantec detector slit variable divergence slit v6 antiscatteringslit v6 2θ range/° 2 ≤ 2θ ≤ 55 step size/° 0.017

2. Preparation of(8-chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine (ComparativeExample)

2,8-Dichloroquinoline (984 mg) is placed in 20 ml tert-butanol.4-(trifluoromethoxy)aniline (743 μL) is then added in presence of 4.6 gCs2CO3, in the presence of 58 mg Xantphos(4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene), and in the presenceof 22 mg Pd(OAc)2. The reaction mixture is then heated at 90° C. andstirred during 20 hours under argon. The reaction mixture isconcentrated under reduced pressure and the resulting residue is dilutedwith ethyl acetate. The organic phase is then washed twice with water,dried on magnesium sulphate, filtered and concentrated under reducedpressure.

The results can be summarized as follows:

3. Preparation of(8-chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine (Free Base)without a Palladium-Catalyst

2,8-Dichloroquinoline (125 g; 0.63 mol) was slurried in4-(trifluoromethoxy)aniline (280 g; 1.58 mol) and isopropanol (240 mL)and the mixture was heated to 90° C. The mixture was stirred for 3-4 hwhen HPLC indicated complete conversion of dichloroquinoline.Thereafter, additional isopropanol (730 mL) was added and the mixturecooled to approx. 40° C. Water (2.5 L) was added slowly and theresulting precipitate was collected by suction filtration. The filtercake was dried under reduced pressure and afterwards recrystallized fromboiling cyclohexane (1.5 L) in order to yield pure product as anoff-white solid.

Yield: 203 g (95%)

Chemical purity: 99.9% (peak area at λ=254 nm).

The identity of(8-chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine was verifiedby 1H-NMR (FIG. 1); FT-IR (FIG. 2) and GC-MS (FIG. 3).

The NMR spectrum was characterized by the following signals:

1H NMR (400 MHz, CDCl3) δ ppm 6.87 (m, 2H); 7.23 (m, 3H); 7.55 (dd,J=8.01, 1.28 Hz, 1H); 7.72 (dd, J=7.52, 1.28 Hz, 1H); 7.90 (m, 3H).

The IR-spectrum was characterized by the following signals:

3406; 1626; 1606; 1535; 1506; 1475; 1425; 1392; 1257; 1217; 1146; 1001;849; 822; 795; 754; 719; 673; 663; 631 cm⁻¹.

The solid state characteristics were investigated by means of DSC andXRPD and is as follows:

The DSC thermogram (FIG. 4) is characterized by a single endotherm withan onset temperature of 120° C. (±2° C.) and a peak temperature of 121σ(±2° C.).

A characteristic x-ray powder diffractogram is given in FIG. 5 and itscharacteristic signals are summarized in the following table:

Index Angle Relative Intensity 1 7.3 100.0% 2 12.0 1.5% 3 13.6 1.5% 414.6 86.4% 5 16.2 1.6% 6 16.8 2.6% 7 17.2 3.7% 8 18.0 1.9% 9 18.3 18.3%10 18.6 8.2% 11 19.4 1.4% 12 20.1 1.9% 13 20.4 1.5% 14 20.7 1.7% 15 22.01.7% 16 22.3 8.0% 17 22.6 4.7% 18 23.0 18.1% 19 23.3 4.8% 20 23.5 11.5%21 24.1 7.1% 22 24.8 35.1% 23 25.5 1.9% 24 27.3 3.0% 25 27.4 2.3% 2628.3 13.8% 27 29.0 8.6% 28 29.5 11.2% 29 30.8 2.5% 30 31.6 1.4% 31 34.11.8% 32 34.7 1.8% 33 35.2 2.6% 34 35.9 0.6% 35 36.6 1.5% 36 37.1 2.0% 3738.9 2.8% 38 39.8 5.6% 39 40.9 3.5% 40 41.5 5.0% 41 42.6 7.4% 42 45.45.4% 43 52.8 4.9%

Major peaks can be seen at angles 7.3, 14.6 and 18.3 with relativeintensities of 100.0%, 86.4% and 18.3%, respectively. Further prominentpeaks can be seen at angles 23.0 and 24.8 with relative intensities of18.1% and 35.1%, respectively. Additional prominent peaks can be seen atangles 28.3 and 29.5 with relative intensities of 13.8% and 11.2%.Finally, remarkable peaks can be seen at angles 18.6, 22.3, 24.1, 29.0and 42.6 with relative intensities of 8.2%, 8.0%, 7.1%, 8.6% and 7.4%,respectively.

4. Comparison of Reaction Conditions

Subsequent experiments were performed as outlined in the followingtable:

eq eq 4- 2,8- (Trifluoro- Reaction Product Dichloro- methoxy)- Temp TimeCon- quinoline aniline Base Solvent [° C.] [h] version^([a]) 1 1.5 4 eq30 eq 140 24 3.5% K₂CO₃ DMF 1 1.5 4 eq 30 eq 140 24 3.5% K₂CO₃ DMSO 11.5 4 eq 30 eq 140 24 1.5% K₂CO₃ NMP 1 1.5 4 eq 40 eq 70 12 — K₂CO₃ MeOH1 2 4 eq 30 eq 70 15 — TEA THF 1 2 4 eq 30 eq 120 15 0.5% TEA BuOH 1 2.5— 10 eq 140 3  67% DMF 1 2.5 — 10 eq 140 3  79% DMSO 1 2.5 — 10 eq 140 3 95% NMP 1 2.5 — 10 eq 70 13 98.5%  MeOH 1 5 — — 130 0.5 99.5%  1 2.5 —5 eq 90 4 99.5%  iPrOH ^([a])estimated by HPLC (230 nm)

DMF, DMSO and NMP solutions performed a rapid conversion of startingmaterial into (8-chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine,but simultaneously the mixtures colored dark or intensive purpure (DMSO)evoked by formation of numerous by-products. In contrast, the conversionin MeOH solution proceeded very clean, but much more time consuming. Atlast the best result was obtained by performing the conversion in pure4-(trifluoromethoxy)aniline (5 eq) which proceeded very fast and cleanin a spot to spot reaction.

An even lower amount of the aniline would enable a satisfying conversiontoo, but 5 equivalents roughly represent the lowest volume forsuccessful dissolution of 2,8-dichloroquinoline. Finally, 2.5 eq of4-(trifluoromethoxy)aniline mixed with 5 eq of isopropanol (IPA) wereestablished successfully. The reaction time was prolonged in anacceptable frame, and the conversion proceeded as clean as in the purereactant.

5. Preparation of(8-chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine (HCl AdditionSalt)

(8-Chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine (5 g; 14.8mmol) was dissolved in diethyl ether (200 mL) at room temperature andHCl (15 mL; 2 M in Et₂O) was added subsequently. The resulting slurrywas stirred for 30 min before the precipitate was filtered off and driedunder reduced pressure. The HCl addition salt was obtained as a paleyellow solid.

Yield: 4.3 g (78%).

Chemical purity: 99.9% (peak area at λ=254 nm).

The identity of the HCl addition salt was verified by 1H-NMR (FIG. 6)and FT-IR (FIG. 7).

The NMR spectrum was characterized by the following signals:

1H NMR (400 MHz, DMSO-d6) δ ppm 7.17 (d, J=8.60 Hz, 1H); 7.29 (t, J=7.82Hz, 1H); 7.34 (d, J=8.60 Hz, 2H); 7.71-7.76 (m, 1H); 7.76-7.80 (m, 1H);8.15 (d, J=8.99 Hz, 1H); 8.32 (m, 2H); 10.14 (m, 2H).

The IR-spectrum was characterized by the following signals:

1645; 1577; 1547; 1504; 1409; 1263; 1199; 1172; 1107; 1014; 999; 987;922; 840; 783; 767; 742; 667; 628 cm⁻¹.

The solid state characteristics were investigated by means of DSC andXRPD and is as follows:

The DSC thermogram (FIG. 16) is characterized by a single broadendotherm with an onset temperature of 154° C. (±5° C.) and a peaktemperature of 170° (±5° C.).

A characteristic x-ray powder diffractogram is given in FIG. 17 and itscharacteristic signals are summarized in the following table:

Index Angle Relative Intensity 1 5.8 100.0% 2 8.2 7.0% 3 11.4 7.0% 411.8 2.9% 5 12.9 26.1% 6 13.0 16.7% 7 13.4 5.5% 8 14.9 13.5% 9 16.298.0% 10 16.7 18.2% 11 17.7 6.3% 12 18.1 8.7% 13 18.6 31.9% 14 21.112.3% 15 22.0 13.4% 16 22.9 13.2% 17 23.7 18.0% 18 24.4 14.0% 19 24.728.7% 20 25.5 86.2% 21 25.9 39.7% 22 27.5 13.4% 23 27.7 30.7% 24 28.313.9% 25 34.0 13.4% 26 35.9 11.5% 27 37.7 13.7% 28 43.6 13.3%

6. Preparation of(8-chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine (H₂SO₄Addition Salt)

(8-Chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine (5 g; 14.8mmol) was dissolved in diethyl ether (200 mL) at room temperature andH2SO4 (0.9 mL; 16.2 mmol) was added subsequently. The resulting slurrywas stirred for 30 min before the precipitate was filtered off and driedunder reduced pressure. The H₂SO₄ addition salt was obtained as a graysolid.

Yield: 6.4 g (99%).

Chemical purity: 99.9% (peak area at λ=254 nm).

The identity of the H₂SO₄ addition salt was verified by ¹H-NMR (FIG. 8)and FT-IR (FIG. 9).

The NMR spectrum was characterized by the following signals:

1H NMR (400 MHz, DMSO-d6) δ ppm 7.17 (d, J=8.93 Hz, 1H); 7.23-7.46 (m,3H); 7.75-7.81 (m, 2H); 8.17 (d, J=8.93 Hz, 1H); 8.30 (m, 2H); 9.41 (brs, 2H); 9.94 (s, 1H)

The IR-spectrum was characterized by the following signals:

1660; 1508; 1269; 1144; 1018; 993; 864; 746; 669 cm⁻¹.

The solid state characteristics were investigated by means of DSC andXRPD and is as follows:

The DSC thermogram (FIG. 18) is characterized by a single broadendotherm with an onset temperature of 209° C. (±5° C.) and a peaktemperature of 214° (±5° C.).

A characteristic x-ray powder diffractogram is given in FIG. 19 and itscharacteristic signals are summarized in the following table:

Index Angle Relative Intensity 1 5.8 100.0% 2 8.2 7.0% 3 11.4 7.0% 411.8 2.9% 5 12.9 26.1% 6 13.0 16.7% 7 13.4 5.5% 8 14.9 13.5% 9 16.298.0% 10 16.7 18.2% 11 17.7 6.3% 12 18.1 8.7% 13 18.6 31.9% 14 21.112.3% 15 22.0 13.4% 16 22.9 13.2% 17 23.7 18.0% 18 24.4 14.0% 19 24.728.7% 20 25.5 86.2% 21 25.9 39.7% 22 27.5 13.4% 23 27.7 30.7% 24 28.313.9%

7. Preparation of(8-chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine (besylateAddition Salt)

(8-Chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine (5 g; 14.8mmol) was dissolved in diethyl ether (200 mL) at room temperature andbenzenesulfonic acid (2.57 g; 16.2 mmol) dissolved in dichloromethane(10 mL) was added subsequently. The resulting slurry was stirred for 30min before the precipitate was filtered off and dried under reducedpressure. The PhSO₃H addition salt was obtained as a pale yellow solid.

Yield: 7.2 g (98.2%).

Chemical purity: 99.9% (peak area at λ=254 nm).

The identity of the besylate addition salt was verified by 1H-NMR (FIG.10) and FT-IR (FIG. 11).

The NMR spectrum was characterized by the following signals:

1H NMR (400 MHz, DMSO-d6) δ ppm 7.17 (d, J=8.93 Hz, 1H); 7.23-7.43 (m,6H); 7.56-7.67 (m, 2H) 7.78-7.81 (m, 2H); 8.17 (d, J=9.05 Hz, 1H);8.24-8.38 (m, 2H); 9.96 (s, 1H) 11.98 (br s, 1H).

The IR-spectrum was characterized by the following signals:

1647; 1506; 1151; 1116; 1028; 1010; 995; 923; 831; 758; 748; 725; 696;669; 607 cm-1.

The solid state characteristics were investigated by means of DSC andXRPD and is as follows:

The DSC thermogram (FIG. 20) is characterized by a single endotherm withan onset temperature of 153° C. (±5° C.) and a peak temperature of 154°(±5° C.).

A characteristic x-ray powder diffractogram is given in FIG. 21 and itscharacteristic signals are summarized in the following table:

Index Angle Relative Intensity 1 6.7 100.0% 2 10.2 10.0% 3 10.7 8.5% 411.5 3.9% 5 11.9 21.5% 6 12.9 18.5% 7 13.5 32.8% 8 14.1 3.3% 9 14.5 5.3%10 15.1 2.0% 11 15.3 2.3% 12 15.9 4.2% 13 16.3 11.3% 14 16.6 4.7% 1517.0 40.2% 16 17.3 3.2% 17 17.9 23.8% 18 17.9 24.5% 19 18.3 58.5% 2019.4 26.7% 21 20.2 15.6% 22 20.5 41.8% 23 21.1 7.4% 24 21.8 4.7% 25 22.323.5% 26 22.9 14.7% 27 23.3 29.9% 28 23.9 43.2% 29 24.3 18.6% 30 24.95.6% 31 25.6 17.1% 32 26.0 11.6% 33 26.7 14.7% 34 27.2 4.8% 35 28.612.9% 36 29.1 4.8% 37 29.8 7.5% 38 30.0 10.0% 39 30.4 14.3% 40 30.9 5.1%41 32.2 4.8% 42 34.8 4.5% 43 38.2 5.7% 44 38.9 6.3% 45 42.8 9.5% 46 43.59.1%

8. Preparation of(8-chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine (tosylateAddition Salt)

(8-Chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine (5 g; 14.8mmol) was dissolved in diethyl ether (200 mL) at room temperature andtoluenesulfonic acid (3.44 g; 17.7 mmol) dissolved in dichloromethane(10 mL) and methanol (2 mL) was added subsequently. The resulting slurrywas stirred for 30 min before the precipitate was filtered off and driedunder reduced pressure. The TolSO₃H addition salt was obtained as a paleyellow solid.

Yield: 7.5 g (99.4%).

Chemical purity: 99.9% (peak area at λ=254 nm).

The identity of ABX-464-tosylate was verified by 1H-NMR (FIG. 12) andFT-IR (FIG. 13).

The NMR spectrum was characterized by the following signals:

1H NMR (400 MHz, DMSO-d6) δ ppm 2.29 (s, 3H); 7.12-7.18 (m, 3H);7.24-7.42 (m, 3H); 7.50 (d, J=8.07 Hz, 2H); 7.75-7.81 (m, 2H); 8.17 (d,J=8.93 Hz, 1H); 8.30 (m, 2H); 9.96 (s, 1H); 11.00 (br s, 1H).

The IR-spectrum was characterized by the following signals:

1649; 1593; 1508; 1416; 1203; 1144; 1120; 1105; 1032; 1020; 1009; 993;924; 833; 822; 746; 712; 681; 667 cm⁻¹.

The solid state characteristics were investigated by means of DSC andXRPD and is as follows:

The DSC thermogram (FIG. 22) is characterized by a single endotherm withan onset temperature of 172° C. (±5° C.) and a peak temperature of 173°(±5° C.).

A characteristic x-ray powder diffractogram is given in FIG. 23 and itscharacteristic signals are summarized in the following table:

Index Angle Relative Intensity 1 6.2 100.0% 2 9.1 3.6% 3 11.1 1.2% 412.5 1.5% 5 14.5 7.1% 6 15.4 2.4% 7 17.1 2.6% 8 17.5 6.0% 9 18.5 9.4% 1019.2 15.7% 11 19.8 8.6% 12 20.6 10.1% 13 21.3 12.1% 14 22.3 8.7% 15 23.01.7% 16 23.7 1.6% 17 24.2 8.0% 18 25.0 3.5% 19 25.5 9.6% 20 25.8 4.3% 2126.3 2.0% 22 26.7 1.9% 23 28.6 5.2% 24 31.0 3.2% 25 31.4 2.2% 26 33.31.8% 27 34.4 2.2% 28 36.0 5.0% 29 37.0 3.7% 30 37.8 5.8% 31 42.3 3.6% 3242.8 5.2% 33 44.4 4.2%

9. Preparation of(8-chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine (hemiedisylateAddition Salt)

(8-Chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine (2 g; 5.9mmol) was dissolved in diethyl ether (80 mL) at room temperature andethanedisulfonic acid (0.74 g; 3.1 mmol) dissolved in acetone (6 mL) wasadded subsequently. The resulting slurry was stirred for 30 min beforethe precipitate was filtered off and dried under reduced pressure. TheEt(SO₃H)₂ addition salt was obtained as a pale yellow solid.

Yield: 2.11 g (82%).

Chemical purity: 99.9% (peak area at λ=254 nm).

The identity of the hemiedisylate addition salt was verified by 1H-NMR(FIG. 14) and FT-IR (FIG. 15).

The NMR spectrum was characterized by the following signals:

1H NMR (400 MHz, DMSO-d6) δ ppm 2.76 (s, 2H); 7.17 (d, J=8.93 Hz, 1H);7.23-7.42 (m, 3H); 7.75-7.81 (m, 2H); 8.17 (d, J=8.93 Hz, 1H); 8.30 (m,2H); 9.97 (s, 1H); 10.87 (br s, 1H).

The IR-spectrum was characterized by the following signals:

1649; 1589; 1504; 1224; 1146; 1049; 1022; 833; 744; 665 cm-1.

The solid state characteristics were investigated by means of DSC andXRPD and is as follows:

The DSC thermogram (FIG. 24) is characterized by a broad singleendotherm with an onset temperature of 142° C. (±5° C.) and a peaktemperature of 173° (±5° C.).

A characteristic x-ray powder diffractogram is given in FIG. 25 and itscharacteristic signals are summarized in the following table:

Index Angle Relative Intensity 1 6.4 60.2% 2 9.4 8.9% 3 10.1 13.2% 412.5 15.6% 5 12.7 19.0% 6 12.9 32.1% 7 14.0 50.2% 8 14.9 19.5% 9 15.219.5% 10 15.8 8.0% 11 16.0 8.5% 12 17.5 49.3% 13 18.2 39.5% 14 19.458.5% 15 20.0 16.1% 16 20.4 76.4% 17 21.0 30.4% 18 22.2 11.7% 19 22.411.7% 20 23.1 35.6% 21 23.5 57.0% 22 23.9 16.6% 23 24.7 17.7% 24 25.6100.0% 25 26.0 63.3% 26 26.4 39.6% 27 27.3 47.4% 28 28.1 12.4% 29 28.614.3% 30 31.2 13.7% 31 32.0 9.9% 32 32.4 10.3% 33 33.5 9.7% 34 35.0 9.3%35 35.5 9.5%

10. Aqueous Solubility

The solubility properties of the generated solid states were studied infour different aqueous buffers with distinct pH values. Approximately250 mg of each sample was mixed with 2.5 ml solvent and stirred. Thesolubility was determined at 15 min 5 and 1 h.

It turned out that most of the acid addition salts showed very goodsolubility in aqueous solutions. A second result is, that the acidaddition salts with inorganic counterion (HCl, H₂SO₄) exhibit first-ratesolubility. The following table presents a summary of the results of allanalyzed samples:

Solubility [mg/mL] free tosyl- hemi- base HCl H₂SO₄ besylate ateedisylate 0.01N 15 min 0.003 0.116 0.089 0.023 0.006 0.075 HCl  1 h0.004 0.147 0.152 0.032 0.010 0.065 pH ~2.2 20 mM 15 min 0 0.074 0.0930.024 0 0.048 Na-  1 h 0 0.136 0.139 0.016 0.003 0.050 acetate pH 4.5 50mM 15 min 0 0.068 0.035 0.003 0 0.018 KH₂PO₄  1 h 0 0.104 0.114 0.007 00.023 pH 6.8 FaSSiF 15 min 0.064 0.111 0.109 0.077 0.030 — (SIF-  1 h0.061 0.198 0.157 0.045 0.013 — powder)

11. Hygroscopicity

The hygroscopicity was determined by Dynamic Vapor Sorption Analysis(DVS). Approximately 200 mg of each solid state were weight on a sampleplate and subjected to the apparatus. The humidity inside was varied ina range from 0 to 95% RH and the mass change (dm [%]) of the samplesmeasured continuously.

It turned out that the free base absorbs more or less not any humidity.The same applies for the tosylate salt, whereas besylate and sulfateexhibit at least a low hygroscopicity with up to 1.9 and 3.2% weightincrease, respectively. But it was demonstrated that this water uptakeis reversible at least and not or only minor (besylate) associated withchanges of the crystalline form. An opposing behavior was observed forthe hemiedisyalte and hydrochloride salt, where a weight increase wasdetected that even was irreversible. Moreover, this water absorption isclosely connected with significant changes of the initial crystallineform. The following table presents a summary of the relative weightchange observed during the DVS experiment (FIG. 26-31):

Relative weight change (dm) [%] RH [%] 40 → 0 → 75 → 95 → 40 → 0 → 35Free base 0 0 0.02 0.15 0.03 0.02 0.02 (FIG. 25) HCl salt 0 −0.11 1.714.3 7.8 2.8 5.1 (FIG. 26) H₂SO₄ salt 0 −0.11 0.32 3.2 0.03 −0.14 −0.04(FIG. 27) Besylate salt 0 −0.04 0.19 1.9 1.1 −0.09 1.0 (FIG. 28)Tosylate salt 0 −0.05 0.05 0.24 −0.03 −0.09 −0.05 (FIG. 29)Hemiedisylate salt 0 −0.65 0.74 36.2 3.5 0.4 2.9 (FIG. 30)

1. A process for preparing a compound of formula (I)

wherein: R independently means a hydrogen atom, a halogen atom or agroup selected from a (C₁-C₃)alkyl group, a —NR₁R₂ group, a(C₁-C₃)fluoroalkoxy group, a phenoxy group or a (C₁-C₄)alkoxy group; R′is a hydrogen atom, a halogen atom except fluorine, or a group selectedfrom a (C₁-C₃)alkyl group; R″ is a hydrogen atom or a (C₁-C₄)alkylgroup; R′″ is a hydrogen atom, a halogen atom, or a group selected froma (C₁-C₃)alkyl group or a (C₁-C₄)alkoxy group; n is 1, 2 or 3; and n′ is1 or 2; which comprises the step of reacting a compound of formula (II)

wherein: R′, R′″ and n′ are defined as in formula (I); and L means aleaving group, preferably selected from a halogen atom, in particularselected from a fluorine atom, a chlorine atom or a bromine atom; with acompound of formula (III)

wherein R″, R, and n are defined as in formula (I); and wherein thecompound of formula (III) is present in excess and no metal catalyst ispresent.
 2. The process according to claim 1, wherein R is a(C₁-C₃)fluoroalkoxy group; R′ is a chlorine atom or a bromine atom; R″is a hydrogen atom; R′″ is a hydrogen atom, a chlorine atom or a bromineatom; and n and n′ are
 1. 3. The process according to claim 1, whereinthe reaction is carried out in the presence of an (C₁-C₄)alcohol.
 4. Theprocess according to claim 1, wherein the reaction is carried out with 1mole of compound (II) and 2-5 mole of compound (III.
 5. The processaccording to claim 1, further comprising the step of precipitating thecompound of formula (I) by adding water.
 6. The process according toclaim 5, further comprising the step of recrystallizing, and optionallydrying, the compound of formula (I).
 7. The process according to claim6, further comprising the step of preparing a pharmaceuticallyacceptable salt of the compound of formula (I).
 8. The process accordingto claim 1, further comprising the step of formulating the compound offormula (I), and optionally its pharmaceutically acceptable salt, with apharmaceutically acceptable carrier.
 9. A polymorphic form of the freebase of (8-chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine,characterized by a single endotherm with an onset temperature of 120° C.(±2° C.) and a peak temperature of 121° (±2° C.) in the DSC thermogramand/or characterized by characteristic signals in the x-ray powderdiffractogram at angles 7.3, 14.6 and 24.8.
 10. The polymorphic form ofthe free base of(8-chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine according toclaim 9, characterized by characteristic signals in the x-ray powderdiffractogram at angles 7.3, 14.6, 18.3, 23.0 and 24.8.
 11. A mineralacid or sulfonic acid salt of(8-chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine.
 12. Themineral acid salt of claim 11, wherein the mineral acid is selected fromhydrochloric acid or sulfate acid.
 13. The sulfonic acid salt of claim11, wherein the sulfonic acid is selected from an alkylsulfonic acid orarylsulfonic acid.
 14. A pharmaceutical composition containing a mineralacid or sulfonic acid salt of claim 11 and a pharmaceutically acceptablecarrier.
 15. The pharmaceutical composition of claim 14 for use in amethod for treating an HIV infection.
 16. The process according to claim1 wherein: R is a chlorine atom or a bromine atom; R″ is a hydrogenatom; R′″ is a hydrogen atom, a chlorine atom or a bromine atom; n is 1or 2; n′ is 1; and L is a fluorine atom or a chlorine atom.
 17. Theprocess according to claim 1 wherein: R′ is a chlorine atom R is atrifluoromethoxy group; R″ and R′″ are independently a hydrogen atom;and n and n′ are 1,
 18. The process according to claim 1 whereincompound (I) is(8-chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine.
 19. Theprocess according to claim 3, wherein the (C₁-C₄)alcohol is butanol orpropanol.
 20. The process according to claim 3, wherein the reaction iscarried out at a temperature between 25° C. and 130° C.
 21. The processaccording to claim 20, wherein the reaction is carried out at atemperature between 80° C. and 100° C.
 22. The process according toclaim 3, wherein the reaction is carried out for 0.5 h to 15 h.
 23. Theprocess according to claim 22, wherein the reaction is carried out for 3h to 4 h.
 24. The process according to claim 1, wherein the reaction iscarried out with 1 mole of compound (II), 2-5 mole of an (C₁-C₄)alcohol, and 2-5 mole of compound (III).
 25. The process according toclaim 1, wherein the reaction is carried out with 1 mole of compound(II), 5 mole of an (C₁-C₄) alcohol, and 2-3 mole of compound (III), 26.The process according to claim 1, wherein the reaction is carried outwith 1 mole of compound (II), 5 mole of an (C₁-C₄) alcohol, and 2-3 moleof compound (III) at a temperature of about 90° C.
 27. The polymorphicform of the free base of(8-chloro-quinolin-2-yl)-(4-trifluoromethoxyphenyl)-amine according toclaim 9, characterized by characteristic signals in the x-ray powderdiffractogram at angles 7.3, 14.6, 18.3, 23.0, 24.8, 28.3 and 29.5. 28.The mineral acid salt of claim 11, wherein the mineral acid is inparticular sulfate acid.